MBE Advance Access originally published online on March 11, 2009
Molecular Biology and Evolution 2009 26(6):1357-1367; doi:10.1093/molbev/msp045
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Research Articles |
Population Genomic Analysis of ALMS1 in Humans Reveals a Surprisingly Complex Evolutionary History
* Department of Genome Sciences, University of Washington
Department of Genetics, Rosetta Inpharmatics, LLC,,1 Seattle, WA
E-mail: akeyj{at}u.washington.edu.
Accepted for publication March 8, 2009.
Mutations in the human gene ALMS1 result in Alström Syndrome, which presents with early childhood obesity and insulin resistance leading to Type 2 diabetes. Previous genomewide scans for selection in the HapMap data based on linkage disequilibrium and population structure suggest that ALMS1 was subject to recent positive selection. Through a detailed population genomic analysis of existing genomewide data sets and new resequencing data obtained in geographically diverse populations, we find that the signature of selection at ALMS1 is considerably more complex than what would be expected for an idealized model of a selective sweep acting on a newly arisen advantageous mutation. Specifically, we observed three highly divergent and globally dispersed haplogroups, two of which carry a set of seven derived nonsynonymous single nucleotide polymorphisms that are nearly fixed in Asian populations. Our data suggest that the interaction of human demographic history and positive selection on standing variation in Eurasian populations approximately 15 thousand years ago parsimoniously explains the spectrum of extant ALMS1 variation. These results provide new insights into the evolutionary history of ALMS1 in humans and suggest that selective events identified in genomewide scans may be more complex than currently appreciated.
Key Words: ALMS1 • positive selection • standing variation
1 A Wholly Owned Subsidiary of Merck and Co., Inc.
Sarah Tishkoff, Associate Editor
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